The common theme of this Program Project Grant (PPG) is the acquisition of fundamental knowledge on the growth and differentiation of progenitor cells (PCs). Understanding PC function and the relationship between cardiac PCs and bone marrow progenitor cells (BMPCs) is critical for the implementation of PC categories in the treatment of the chronically decompensated human heart. Theoretically, in a manner comparable to hematopoietic stem cells that repopulate and completely reconstitute the ablated bone marrow, cardiac PCs may be capable of rebuilding the damaged myocardium and converting a severely diseased failing heart into a physiologically functional heart. To accomplish these objectives, we need profound understanding of the biology of resident PCs and we have to determine whether the cardiac PC pool includes distinct classes of primitive cells which have powerful but distinct vasculogenic and myogenic properties. The recognition of a coronary vascular progenitor cell (VPC) that differentiates predominantly into smooth muscle cells and endothelial cells would suggest that the heart has the ability to create the various portions of the coronary circulation, from conductive coronary arteries to capillary structures. Similarly, the characterization of a myocyte progenitor cell (MPC) that acquires prevalently the cardiomyocyte phenotype would suggest that the opportunity exists to restore extensive losses of muscle mass. Various proportions of VPCs and MPCs may be utilized according to the needs of the organ and the uniqueness of the cardiac lesion. By necessity, this information will be obtained initially in small animal models (Project 1), which are particularly suitable for genetic manipulations relevant to the characterization of the effector pathways that regulate the activation and differentiation of PC classes into specific cardiac cell lineages. Concurrently, the presence and therapeutic potential of VPCs and MPCs will be established in large animal models (Projects 2 and 3) to obtain relevant preclinical data. Finally, whether the decompensated human heart possesses functionally competent VPCs and MPCs and whether molecular strategies can be implemented to interfere with the fate of PC categories and enhance their regenerative capacity will be tested (Project 4). Ultimately, the identity of cardiac PC classes and the molecular mechanisms involved in the activation and differentiation of these primitive cells into separate cardiogehic phenotypes will be evaluated to define the efficacy of these cells for the repair of the chronically failing heart.